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WO1993017662A1 - Implants ameliores - Google Patents

Implants ameliores Download PDF

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Publication number
WO1993017662A1
WO1993017662A1 PCT/AU1993/000083 AU9300083W WO9317662A1 WO 1993017662 A1 WO1993017662 A1 WO 1993017662A1 AU 9300083 W AU9300083 W AU 9300083W WO 9317662 A1 WO9317662 A1 WO 9317662A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
implant device
body member
release
central support
Prior art date
Application number
PCT/AU1993/000083
Other languages
English (en)
Inventor
Richard Yu
Original Assignee
Daratech Pty. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daratech Pty. Ltd. filed Critical Daratech Pty. Ltd.
Priority to AU36224/93A priority Critical patent/AU3622493A/en
Publication of WO1993017662A1 publication Critical patent/WO1993017662A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
    • A61D7/00—Devices or methods for introducing solid, liquid, or gaseous remedies or other materials into or onto the bodies of animals

Definitions

  • the present invention relates generally to an implant device for the 5 administration of one or more bioactive molecules to animals including humans.
  • the device may be adapted for continuous release or pulsatile release of the bioactive molecules.
  • An ideal delivery device administers bioactive agents to a target at a level which 10 achieves the desired therapeutic effect.
  • bioactive molecules with short in viv half-lives such as some hormones and proteins
  • it is often desirable for the device to deliver at a constant release rate i.e. zero order kinetics.
  • a membrane-reservoir device may be used.
  • a membrane reservoir device consists of a core of the biologically active material surrounded by a 15 release-rate limiting membrane.
  • the rate at which the drug is released is determined by the geometry of the device and the physico-chemical nature, thickness and surface area of the release-rate limiting membrane (1,2).
  • membrane reservoir 25 devices are not used extensively because of technical difficulties associated with their fabrication in mass production (4).
  • a more serious disadvantage of membrane reservoir devices is the fact that the core active material can be released by dumping whenever the release-rate limiting membrane is ruptured. **" This is highly undesirable in therapeutic treatment.
  • the geometric shape of the delivery device has been modified to compensate for the increasing diffusion distance and decreasing area of the advancing diffusion front.
  • a hemispherical polymer matrix which is coated on all surfaces with an impermeable coating except for an aperture in the flat centre face has been shown to provide a near constant rate of drug release (8).
  • Another example consists of a cylinder with impermeable wall coating and a longitudinal slit opening inward to a concave circular sector cross section.
  • the release rate from this elegant device also showed a substantially uniform rate (9).
  • the increase in diffusional distance and consequently the decrease in diffusion rate have been compensated by the increase in the surface area at the advancing diffusion front.
  • one aspect of the present invention contemplates an implant device capable of releasing an active ingredient in an animal following administration thereto, said implant device comprising as active ingredient at least one type of bioactive molecule, optionally admixed with one or more pharmaceutically acceptable carriers and/or excipients, substantially contained within a core matri of a body member, said body member further comprising a membrane forming a wall around all or part of the core matrix and comprising material which is substantially impervious to the active ingredient and said body member further having at least one portion through which the active ingredient is capable of bein released either directly or after a period of time in a continuous or pulsatile manner.
  • the intended recipient of the implant device is preferably a human, livestock animal including a ruminant animal (e.g. a sheep, cow, horse, pig, goat or donkey), poultry (e.g. chicken, turkey, goose or game bird), a laboratory test animal (e.g. a rabbit, guinea pig or mouse), companion animal (e.g. dog or cat) o a wild animal in the captive or free state.
  • a ruminant animal e.g. a sheep, cow, horse, pig, goat or donkey
  • poultry e.g. chicken, turkey, goose or game bird
  • laboratory test animal e.g. a rabbit, guinea pig or mouse
  • companion animal e.g. dog or cat
  • the bioactive molecule in the active ingredient comprises any native, synthetic or recombinant pharmaceutical agent or food additive or supplement including antigens, antibodies, cytokines, growth promotants, hormones, cancer cell inhibitory molecules or agents, immune stimulants or suppressants, anti-microbial agents including antibiotics, anti-viral agents, vitamins, minerals or inorganic or organic nutrients.
  • the active ingredient may comprise one type of bioactive molecule or may be a mixture of different bioactive molecules.
  • Administration of the implant device may be by any convenient means but is generally by oral ingestion or injection via the intravenous, intraperitoneal, intramuscular, sub-cutaneous or intradermal route.
  • the device may also be surgically implanted or implanted by sub-surgical procedures such as during biopsy procedures.
  • the pharmaceutical carriers and excipients include any and all dispersion media, coatings, antibacterial, anti-fungal and/or antiviral agents and the like as well as salts such as dicalcium phosphate. Additional components which may be included are binders (e.g. gum gragacanth, acacia, corn starch or gelatin), disintegrating agent (e.g. corn starch, potato starch, alginic acid and the like) and/or a lubricant (e.g. magnesium stearate). All such components, carriers and excipients must be substantially pharmaceutically pure and non-toxic in the amounts employed and must be bioc ⁇ mpatible with the bioactive molecules.
  • binders e.g. gum gragacanth, acacia, corn starch or gelatin
  • disintegrating agent e.g. corn starch, potato starch, alginic acid and the like
  • a lubricant e.g. magnesium stearate
  • the amount of bioactive molecule used in a given implant will vary depending on the type of bioactive molecule, condition in the animal being treated and the presence or absence of agonists to the bioactive molecule or antagonists to the condition being treated.
  • an effective amount of bioactive material is employed meaning an amount effective to induce, stimulate, promote or otherwise initiate the immediately intended result.
  • the bioactive molecule is an antigen
  • the effective amount is that required to stimulate an immune response to the antigen.
  • the bioactive molecule will be present in amounts ranging from a few micrograms to gram quantities per implant device.
  • the body member of the implant device may be in any shape including elongate, oval, round, ball, hemispherical, capsule, rod, needle, cylinder, sheet, film or microcapsular shape. Conveniently, the shape is an elongate, cylindrical, rod or needle shape. In a most preferred embodiment, the implant device is elongate or generally cylindrical.
  • the walls encasing the body member are generally membranous or polymeric an are substantially impervious to the active ingredient and body fluid.
  • the body member is elongate, or more preferably generally cylindrical, having terminal portions capable of releasing the active ingredient contained within the core body member.
  • the ends of the body member are open or sealed or partially sealed with a biodegradable polymer or other suitable material such that the end seals will degrade sufficiently to permit the active ingredient to be released.
  • an implant device capable of releasing an active ingredient in an animal following administration thereto, said implant comprising as an active ingredient at least one type of bioactive molecule, optionally admixed with one or more pharmaceutically acceptable carriers and/or excipients, substantially contained within a core matrix of an elongate body member, said body member further comprising a membrane forming a wall around all or part of the core matrix and comprising material which is substantially impervious to the active ingredient and said elongate body member having at least one terminal portion through which the active ingredient is capable of being released either directly or after a period of time in a continuous or pulsatile manner.
  • the elongate body member possesses two terminal portions through which the active material is capable of being released.
  • the active ingredient releasing end or ends of the body member may be open, partially sealed or completely sealed. Where the latter is the case, the end seals are materials capable of degrading or rupturing at some time after administration into die animal.
  • the period of time before this seal is degraded may range from a few minutes to a few hours or even a few days.
  • the present invention contemplates an implant device capable of releasing an active ingredient in an animal following administration thereto, said implant comprising a generally cylindrical or elongate device containing at least one bioactive molecule, optionally admixed with one or more pharmaceutically acceptable carriers and/or excipients, wherein the device is adapted such that a substantial amount of the active material is able to be released via end portions of said device.
  • the body member may comprise a plurality of alternating layers of active ingredient and walls substantially impervious to said active ingredient.
  • die implant device may contain only one type of bioactive molecule or may contain different types of bioactive material, released continuously or in a pulsatile manner.
  • the preferred body member is elongate and more preferably generally cylindrical in shape with terminal portions open, sealed or partially sealed as hereinbefore described.
  • each layer may in turn be exposed to the animal's body fluids or all or most of d e layers may be exposed simultaneously permitting, for example, the release of different active ingredients simultaneously or the same active ingredient in a pulsatile manner.
  • the process for manufacture of the implant device according to tiiis aspect of the invention is conveniently achieved by a cyclical manufacturing process which is repeated until as many layers as required are formed.
  • an implant device capable of releasing an active ingredient in an animal following administration thereto, said implant device comprising as an active ingredient at least one type of bioactive molecule, optionally admixed with one or more pharmaceutically acceptable carriers and/or excipients, substantially contained within a body member comprising a plurality of matrices interspaced by a plurality of layers of material substantially impervious to the active ingredient and said body member coated by a membrane comprising said material and said body member further comprising at least one portion through which the active ingredients in each layer are simultaneously or sequentially capable of being released either directly or over a period of time.
  • the body member is substantially elongate or generally cylindrical and the active ingredients are released through the terminal portions of the elongate or cylindrical body.
  • Each layer may be exposed simultaneously or sequentially.
  • the terminal portions may also be sealed completely or partially with a biodegradable material, which, for example, degrades in the presence of body fluids.
  • Still another aspect of the present invention provides a method of preparing an implant device comprising fabricating a body member containing an active ingredient, said body member having walls substantially impermeable to the activ material and further having a region through which the active ingredient is capable of being released in a controlled manner either directly or after a period of time.
  • the active material is formed on a central support.
  • Reference herein to the coating as being “substantially impermeable” is meant that in the time frame of delivery of active material from the device only a minor proportion is released via the coated walls relative to delivery via the ends of the device.
  • the resultant implant cast of the core body member may range in length from twenty millimetres to a metre long and can then be reduced to smaller segments of the desired lengtii by cutting across the longitudinal axis of die implant. Alternatively, individual segments of desired size and shape may be pre-moulded.
  • the core matrix may be cast, sectioned, coated and tiien separated. All such variations are encompassed by die present invention. Additionally, for manufacture of multiple layers of matrix interspaced witii impervious membrane, the latter may form the core for the next matrix and so on.
  • Figure 1 is a schematic representation of the process of preparing implants according to the invention. The steps involved are casting 1, cast drying 2, coating 3 and cutting 4.
  • Figure 2 illustrates the effect of changes in agar concentration in matrix on release profile.
  • Figure 3 shows the effect of implant length on the release of incorporated haemoglobin from open ended implants.
  • A2, A4, A6, A8, AlO and A20 represent the release profiles from implants of 2, 4, 6, 8, 10 and 20 mm in length.
  • the incorporating matrix contained 3% w/v agar.
  • the plot points represent a summation of implants which have a constant summed length.
  • Figure 4 illustrates the effect of sealing one end of a cylindrical implant, 5 or 10 mm in length, with polymerised n-butyl cyanoacrylate, on the release of haemoglobin.
  • the incorporating matrix contained 3% w/v agar.
  • Figure 5 is a schematic representation of a form of the implant device having multiple alternating layers of active ingredient interspaced with dividing walls of impervious material.
  • a first implant 1 is prepared as in Figure 1 and the process is repeated to result in subsequent layers, e.g. 2, 3.
  • the terminal portions of the multilayered implant device may be open to permit simultaneous contact of the active ingredient with body fluid or one or of the layers may be sealed with a biodegradable material.
  • a central support e.g. a nylon string, polypropylene rod, or surgical suture
  • a central support e.g. a nylon string, polypropylene rod, or surgical suture
  • the inner surface of the mould should be lined with material such as teflon to facilitate cast removal.
  • the mould in a vertical orientation is preferably pressure-filled from the bottom with an admixture of bioactive material, polymeric matrix, and excipient(s) according to the formulation used.
  • the half-cylinder moulds are removed.
  • the fresh cast may be then coated with polylactic acid (PLA)/polyglycolic acid (PLG) (85:15) co-polymer by dipping and air drying to form a water impermeable coating to thereby produce the body member.
  • the dry cast may be coated with a water impermeable co-polymer such as n-butyl cyanoacrylate (3M-Vetbond TM).
  • the surface-coated cylindrical cast is then trimmed to segments of the desired length, usually 10 or 15mm, for use as implants.
  • the two cut ends of each segment individually moulded or sectioned prior to or subsequent to coating may be left open for the release of the bioactive material or one end may be sealed to form an implant releasing only from one end of the implant.
  • the device represents a package of the bioactive material which remains "dormant" for as long as the end cap is intact. This process may be repeated creating a plurality of layers interspersed with active ingredients (see Figure 5).
  • n-butyl cyanoacrylate (3M-VetbondTM) in sealing the ends has been investigated.
  • a 200 mm long cylindrical cast containing haemoglobin as a release indicator was incorporated in a gelatin agar matrix (5% w/v gelatin, 1% w/v agar) and formed on a centrally supported nylon string (diameter - 0.4mm).
  • the cast was air dried at room temperature and then coated by five cycles of dipping and air drying with a solution of PLA/PLG (85:15) co-polymer (100 mg/ml in acetone). The dried cast was then cut into segments 10 mm long.
  • each segment was moisturised by contacting the surface of a drop of distilled water. After being in contact with the water for 3-5 minutes to wet the cut ends, the ends were blotted dry with sorbet paper towel and then coated by contacting body member with the surface of a drop of n-butyl cyanoacrylate on a clear white tile. One crop of n-butyl cyanoacrylate was used for the two cut ends of one segment. The treated segments were allowed to dry at room temperature for a period of 6 hours before testing in vitro or in viva
  • release rate appeared to be time-dependent suggesting a diffusion dominated mechanism with the gelatin agar matrix material used in these trials.
  • release of bioactive from the device of the present invention is less time dependent (zero order) when other matrix material such as poly ortho esters or copolymers of collagen poly (HEMA) hydrogel are used as the incorporating matrices.
  • HEMA collagen poly
  • the release mode of the present device can also be modified by the concentration and composition of the matrix materials. As shown in Figure 2, when the agar concentration in the matrix was lowered, the release was faster and the extent of release higher.
  • Modulation of the release of haemoglobin from gelatin based matrices can be effected by the inclusion of agar but the effect using the amounts of agar shown in Table 2 was complex bearing no apparent direct dependency on the agar concentrations.
  • the implant device of the present invention may result in release of the active ingredient continuously over a period of time through the unsealed ends of the device.
  • a delayed and/ or pulsatile effect may be obtained by sealing the ends with a biodegradable material or by making a body member with multiple layers.
  • Parameters which can modify the release characteristics of the bioactive material including sealing the open ends of the cylindrical device with n-butyl cyanoacrylate (3M-VetbondTM).
  • M-VetbondTM n-butyl cyanoacrylate
  • the release of haemoglobin from this device ca be completely arrested when both ends were treated with cyanoacrylate. The release would be different when one rather than both ends of the cylindrical device was kept open ( Figure 4).
  • Figure 4 shows a comparison of release of incorporated haemoglobin from segments which either have or have not ends sealed with n-butyl cyanoacrylate.
  • the release rate of haemoglobin from segments with one end closed were slower but the duration of continuous release was substantially extended compared to those with both ends open.
  • sealing one end of a segment slowed down the release making it look like coming out from an open end segment twice in length (refer to Figure 3) and at the same time made the release less time dependent.
  • sealing one of the cut ends of segments provides a practical means of modulating the release characteristics of the delivery device. As described earlier, when both ends were sealed, release of the incorporated haemoglobin was completely prevented.
  • the present invention provides such a method for fabricating a device which can release a comprehensive range of bioactive materials including water soluble macro-molecules in a continuous manner using relatively inexpensive non-toxic matrix and polymer material.
  • the method is suitable for fabricating devices of th controlled release of active material including vaccines, animal growth hormones, antibiotics and anthelmintics.
  • the present device also provides the basis on which further refinement or sophistication of release can be effected.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un implant capable de libérer un ingrédient actif dans un animal consécutivement à son implantation, ledit implant comprenant comme ingrédient actif au moins un type de molécule bioactive, le cas échéant mélangée avec un ou plusieurs vecteurs et/ou excipients acceptables sur le plan pharmaceutique et contenus sensiblement dans une matrice centrale de l'implant, ledit implant comprenant en outre une membrane qui forme une paroi autour de la totalité ou d'une partie de la matrice centrale, qui est constituée d'un produit sensiblement imperméable à l'ingrédient actif et qui comporte au moins une portion à travers laquelle l'ingrédient actif peut être libéré soit directement, soit après un certain temps, d'une manière continue ou pulsée.
PCT/AU1993/000083 1992-03-02 1993-03-01 Implants ameliores WO1993017662A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU36224/93A AU3622493A (en) 1992-03-02 1993-03-01 Improved implants

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPL113592 1992-03-02
AUPL1135 1992-03-02

Publications (1)

Publication Number Publication Date
WO1993017662A1 true WO1993017662A1 (fr) 1993-09-16

Family

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Family Applications (1)

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PCT/AU1993/000083 WO1993017662A1 (fr) 1992-03-02 1993-03-01 Implants ameliores

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WO (1) WO1993017662A1 (fr)
ZA (1) ZA931481B (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003159A1 (fr) * 1992-07-31 1994-02-17 Daratech Pty. Ltd. Implants a liberation regulee
DE19649100A1 (de) * 1996-11-27 1998-06-04 Lohmann Therapie Syst Lts Verfahren zur verlustarmen Herstellung wirkstoffhaltiger scheibenförmiger Formkörper und diese enthaltende transdermale therapeutische Systeme
WO1999044583A3 (fr) * 1998-03-02 1999-11-11 Applied Vaccine Technologies C Procedes et dispositifs modulant la reponse immunitaire
WO2003051328A1 (fr) * 2001-12-18 2003-06-26 Novo Nordisk A/S Micro implant a dose solide
US6958158B2 (en) 2001-05-11 2005-10-25 Ortho-Mcneil Pharmaceutical, Inc. Immune modulation device for use in animals
WO2006078320A3 (fr) * 2004-08-04 2006-10-19 Brookwood Pharmaceuticals Inc Procede de production de systemes d'administration, et systemes d'administration
US7666844B2 (en) 1999-04-16 2010-02-23 Novo Nordisk A/S Dry mouldable drug formulation
US8454997B2 (en) 2001-12-18 2013-06-04 Novo Nordisk A/S Solid dose micro implant
WO2025163335A1 (fr) * 2024-02-02 2025-08-07 Imphatec Ltd Implant pour l'administration d'un médicament

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE902458A (fr) * 1984-05-24 1985-09-16 Damon Biotech Inc Procede pour produire des anticorps par induction d'une reponse immunitaire a l'action de cellules encapsulees secretant des antigenes.
AU2044988A (en) * 1987-08-08 1989-03-02 Merck Sharp & Dohme B.V. Contraceptive implant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE902458A (fr) * 1984-05-24 1985-09-16 Damon Biotech Inc Procede pour produire des anticorps par induction d'une reponse immunitaire a l'action de cellules encapsulees secretant des antigenes.
AU2044988A (en) * 1987-08-08 1989-03-02 Merck Sharp & Dohme B.V. Contraceptive implant

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 109, No. 16, issued 17 October 1988, Columbus, Ohio, USA, SMITH, THOMAS J et al., "Poly (Vinyl Alcohol) Membrane Permeability Characteristics of 5-Fluorouracil", page 372, the Abstract No. 134910z. *
CHEMICAL ABSTRACTS, Vol. 115, No. 21, issued 25 November 1991, Columbus, Ohio, USA, NEFTEL, FREDERIC, "Implantable Device for Measurement of Blood Glucose Levels", page 516, the Abstract No. 227769z. *
CHEMICAL ABSTRACTS, Vol. 117, No. 8, issued 24 August 1992, Columbus, Ohio, USA, ISHII RUMIKO et al., "Drug Delivery System of 5-Flurouracil", page 430, the Abstract No. 76404q. *
DERWENT ABSTRACT, Accession No. 85-242804/40, Class B04D 16; & BE,A,902 458 (DAMON BIOTEC INC), 16 September 1985. *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003159A1 (fr) * 1992-07-31 1994-02-17 Daratech Pty. Ltd. Implants a liberation regulee
DE19649100A1 (de) * 1996-11-27 1998-06-04 Lohmann Therapie Syst Lts Verfahren zur verlustarmen Herstellung wirkstoffhaltiger scheibenförmiger Formkörper und diese enthaltende transdermale therapeutische Systeme
WO1999044583A3 (fr) * 1998-03-02 1999-11-11 Applied Vaccine Technologies C Procedes et dispositifs modulant la reponse immunitaire
US7666844B2 (en) 1999-04-16 2010-02-23 Novo Nordisk A/S Dry mouldable drug formulation
US8518430B2 (en) 1999-04-16 2013-08-27 Novo Nordisk A/S Dry mouldable drug formulation
US8084053B2 (en) 1999-04-16 2011-12-27 Novo Nordisk A/S Dry mouldable drug formulation
US6958158B2 (en) 2001-05-11 2005-10-25 Ortho-Mcneil Pharmaceutical, Inc. Immune modulation device for use in animals
US7094419B2 (en) 2001-05-11 2006-08-22 Tenhuisen Kevor S Method of obtaining immune cells from an animal
WO2003051328A1 (fr) * 2001-12-18 2003-06-26 Novo Nordisk A/S Micro implant a dose solide
US8454997B2 (en) 2001-12-18 2013-06-04 Novo Nordisk A/S Solid dose micro implant
JP2005517651A (ja) * 2001-12-18 2005-06-16 ノボ・ノルデイスク・エー／エス 固形投与マイクロインプラント
AU2005325213B2 (en) * 2004-08-04 2010-10-07 Evonik Operations Gmbh Methods for manufacturing delivery devices and devices thereof
WO2006078320A3 (fr) * 2004-08-04 2006-10-19 Brookwood Pharmaceuticals Inc Procede de production de systemes d'administration, et systemes d'administration
EP2594259A1 (fr) * 2004-08-04 2013-05-22 Brookwood Pharmaceuticals, Inc. Procédé de production de systèmes d'administration, et systèmes d'administration
WO2025163335A1 (fr) * 2024-02-02 2025-08-07 Imphatec Ltd Implant pour l'administration d'un médicament

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Publication number Publication date
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